US20090246135A1 - Diagnostic agent - Google Patents

Diagnostic agent Download PDF

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Publication number
US20090246135A1
US20090246135A1 US12/310,019 US31001907A US2009246135A1 US 20090246135 A1 US20090246135 A1 US 20090246135A1 US 31001907 A US31001907 A US 31001907A US 2009246135 A1 US2009246135 A1 US 2009246135A1
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US
United States
Prior art keywords
acid
diagnostic agent
colorant
wall
lesion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/310,019
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English (en)
Inventor
Yoshirou Kawahara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Okayama University NUC
Original Assignee
Okayama University NUC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Assigned to NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY reassignment NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAWAHARA, YOSHIROU
Publication of US20090246135A1 publication Critical patent/US20090246135A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/273—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the upper alimentary canal, e.g. oesophagoscopes, gastroscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence

Definitions

  • the present invention relates to a diagnostic agent to be used in endoscopic observation of the inner wall of a gastrointestine.
  • JP 10-194998 A discloses a thickener and a living body marking preparation for operations which contains an intermediate color or cool color colorant applicable to the living body. This document reports that injecting the living body marking preparation to a site to be resected with a syringe allow the resection area to become clear during a surgical operation.
  • Patent document 1 JP 10-194998 A
  • the present invention was made in order to solve the above-described problems.
  • the invention intends to provide a diagnostic agent which makes it possible, by being sprinkled to the inner wall of a gastrointestine in endoscopic observation, to observe clearly a lesion difficult to be determined.
  • a diagnostic agent for being sprinkled to the inner wall of a gastrointestine in endoscopic observation comprising an acidic aqueous solution of pH 1 to 5 containing a colorant.
  • the colorant is an intermediate color or cool color colorant.
  • the acidic aqueous solution contain at least one acid selected from the group consisting of a carboxylic acid, hydrochloric acid, sulfuric acid and phosphoric acid. It is preferable that the acid is at least one carboxylic acid selected from the group consisting of acetic acid, malic acid and citric acid. Moreover, it is also preferable that the concentration of the carboxylic acid is 0.01 to 1 mol/L.
  • the diagnostic agent of the present invention can make it possible, by being sprinkled to the inner wall of a gastrointestine at the time of endoscopic observation, to observe clearly a lesion difficult to be determined. It, therefore, can be preferably used to detection of early cancer or the like.
  • FIG. 1 is a photograph of the inner wall of the stomach observed with an endoscope in Test Example 1.
  • FIG. 2 is a photograph of the inner wall of the stomach observed after sprinkling only an aqueous indigo carmine solution in Test Example 1.
  • FIG. 3 is a photograph of the inner wall of the stomach observed after sprinkling a diagnostic agent of the present invention in Test Example 1.
  • FIG. 4 is a photograph of the inner wall of the stomach observed with an endoscope in Test Example 2.
  • FIG. 5 is a photograph of the inner wall of the stomach observed after sprinkling only an aqueous indigo carmine solution in Test Example 2.
  • FIG. 6 is a photograph of the inner wall of the stomach observed after sprinkling a diagnostic agent of the present invention in Test Example 2.
  • the diagnostic agent of the present invention is a diagnostic agent for being sprinkled to the inner wall of a gastrointestine in endoscopic observation, comprising an acidic aqueous solution of pH 1 to 5 containing a colorant.
  • the diagnostic agent of the present invention is sprinkled to the inner wall of a gastrointestine when the gastrointestine is observed with an endoscope.
  • the diagnostic agent can make it easier to observe lesions on the basis of the degree of the adhesion of the agent to the surface of the inner wall of a gastrointestine.
  • the method of sprinkling is not particularly restricted as long as the diagnostic agent of the present invention can be supplied to the inner wall of the gastrointestine, and it may be applying, spraying, or the like.
  • the term “gastrointestine” collectively refers to organs for digesting and absorbing foods, including liver, gallbladder and pancreas as well as gastrointestinal tract including esophagus, stomach, small intestine and large intestine or the like.
  • the diagnostic agent of the present invention can be used suitably for stomach and Barrett's esophagus, the inner surface of which is composed of columnar epithelium.
  • a columnar epithelium is a tissue which is particularly suitable to be applied the diagnostic agent of the present invention because it has a characteristic that its surface, which ordinarily is transparent, becomes whitish on change in pH, particularly when the acidity has become strong.
  • the diagnostic agent of the present invention contains a colorant. Because of this fact, the amount of the diagnostic agent having adhered to the surface to be observed is emphasized by the difference in colorant concentration, so that the margin line between a lesion and a normal mucosa can be observed clearly. Moreover, it becomes easy to observe irregularities on the surface.
  • the colorant preferably is of an intermediate color or cool color, and more preferably is of a cool color.
  • the intermediate color as referred to herein include colors other than warm colors and cool colors and examples thereof include green, purple and brown. Examples of the cool colors include blue.
  • the form of the colorant to be used in the present invention is not particularly restricted and it may be either a dye or a pigment, it is preferable, from the viewpoint of the easiness with which a washing operation is performed after the sprinkling, that the colorant is in the form of a dye.
  • the colorant to be used in the present invention is not particularly restricted, and examples thereof include Fast Green (Food Green No. 3), copper chlorophyll, sodium copper chlorophyllin, sulfobromophthalein sodium, Indocyanine Green, Methylene Blue, Brilliant Blue (Food Blue No. 1), indigo carmine (Food Blue No. 2), gardenia blue, toluidine blue, pyoktanin blue, and caramel colors.
  • the colorant preferably is indigo carmine (Food Blue No. 2), gardenia blue, or a caramel color, and more preferably is indigo carmine (Food Blue No. 2) or gardenia blue, each of which is a cool color colorant.
  • the concentration of the colorant to be used in the present invention may vary depending upon the type or the application site of the colorant, it is preferable, from the viewpoint that the margin line between a lesion and a normal mucosa can be observed clearly, that the colorant concentration is within the range of 0.1 to 200 mmol/L.
  • concentration of the colorant is less than 0.1 mmol/L, it may become difficult to observe the difference from the color of the inner wall of a gastrointestine. It, therefore, is more preferable that the colorant concentration is 1 mmol/L or more.
  • the concentration of colorant exceeds 200 mmol/L, the color contrast decreases and, as a result, it may become difficult to observe the color contrast. It, therefore, is more preferable that the colorant concentration is 100 mmol/L or less.
  • the diagnostic agent of the present invention is composed of an acidic aqueous solution of pH 1 to 5 containing a colorant. Because of the fact that pH is within such a range, in many cases when the diagnostic agent of the present invention is sprinkled, secretion of mucus is promoted at a lesion, especially a lesion having cancer cells while almost no mucus is secreted at a normal mucosa. As a result, the secreted mucus makes a solution containing a colorant less prone to adhere to lesions, so that it becomes possible to clearly observe the margin line between a lesion and a normal mucosa on the basis of the difference in contrast of the colorant.
  • the margin line between a lesion and a normal mucosa is prone to become clear.
  • the pH is preferably 2 or more, and is more preferably 3 or more.
  • the pH is preferably 4 or less because when the pH is greater than 5, the mucus secretion at a lesion may be promoted insufficiently and, as a result, the margin line between the lesion and a normal mucosa may become unclear.
  • the solution containing a colorant is acidic. It has been known that the surface of a lesion and the surface of a normal mucosa become whitish to different degrees when an aqueous acetic acid solution is sprinkled to the inner wall of a gastrointestine. Observations, however, cannot be performed easily on the basis of only this fact. The present inventor has confirmed that a colorant is less prone to adhere either to lesions or to normal mucosa when an aqueous indigo carmine solution has been sprinkled following the sprinkle of an aqueous acetic acid solution. Therefore, it is important that the solution containing a colorant is acidic.
  • the kind of the acidic aqueous solution is not particularly restricted, it is preferable that the solution contain an acid selected from among carboxylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and so on.
  • an acid selected from among carboxylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and so on.
  • a carboxylic acid is used preferably.
  • carboxylic acid to be used is not particularly restricted, moonocarboxylic acids, such as acetic acid, propionic acid and butyric acid; oxymonocarboxylic acids, such as lactic acid, glycolic acid and gluconic acid; polycarboxylic acids, such as oxalic acid, succinic acid, glutaric acid, adipic acid, and fumaric acid; hydroxypolycarboxylic acids, such as malic acid and citric acid, and so on can be used.
  • moonocarboxylic acids such as acetic acid, propionic acid and butyric acid
  • oxymonocarboxylic acids such as lactic acid, glycolic acid and gluconic acid
  • polycarboxylic acids such as oxalic acid, succinic acid, glutaric acid, adipic acid, and fumaric acid
  • hydroxypolycarboxylic acids such as malic acid and citric acid, and so on
  • the concentration of the carboxylic acid in use in the diagnostic agent of the present invention is not particularly limited, it is more preferably 0.01 to 1 mol/L.
  • the concentration of the carboxylic acid preferably is 0.05 mol/L or more because when the concentration of the carboxylic acid is less than 0.01 mol/L, the mucus secretion at a lesion may be promoted insufficiently and, as a result, the margin line between the lesion and a normal mucosa may become unclear.
  • the concentration of the carboxylic acid is more preferably 0.5 mol/L or less because when the concentration of the carboxylic acid is greater than 1 mol/L, the inner wall of a gastrointestine may be damaged.
  • the use of the diagnostic agent of the present invention makes it possible to detect and observe early gastrointestinal cancers or the like, which have heretofore been difficult to be determined.
  • the diagnostic agent of the present invention can be used suitably for early gastric cancer or early Barrett's esophagus cancer particularly among the gastrointestinal cancers.
  • a diagnostic agent of the present invention was obtained by mixing 25 ml of a 0.4 wt % aqueous indigo carmine solution (produced by Daiichi Pharmaceutical Co., Ltd.) and 15 ml of a 1.5 wt % aqueous acetic acid solution.
  • the resulting diagnostic agent had an indigo carmine concentration of 5.3 mmol/L, an acetic acid concentration of 0.1 mol/L, and a pH of 3.0.
  • FIG. 1 An upper gastrointestinal tract videoendoscope was inserted into the stomach of a 68-year-old male patient and an endoscopy was conducted. As a result, however, the presence of lesions could not be confirmed clearly as shown in FIG. 1 . Only a 0.4 wt % aqueous indigo carmine solution (produced by Daiichi Pharmaceutical Co., Ltd.) was sprinkled to the inner wall of the stomach. As a result, a suspicious lesion was found as shown in FIG. 2 , but no lesion could be determined clearly. The inner wall of the stomach was washed with distilled water for injection and then the diagnostic agent of the present invention prepared by the method described above. As a result, a red depressed lesion was observed clearly, as shown in FIG. 3 , in a blue-stained normal mucosa as a background. The lesion was removed by endoscopic submucosal dissection, so that a well differentiated adenocarcinoma was confirmed.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pathology (AREA)
  • Molecular Biology (AREA)
  • Optics & Photonics (AREA)
  • Surgery (AREA)
  • Medical Informatics (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • Physiology (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US12/310,019 2006-08-08 2007-07-31 Diagnostic agent Abandoned US20090246135A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2006215437 2006-08-08
JP2006-215437 2006-08-08
PCT/JP2007/065012 WO2008018327A1 (fr) 2006-08-08 2007-07-31 Agent de diagnostic

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/065012 A-371-Of-International WO2008018327A1 (fr) 2006-08-08 2007-07-31 Agent de diagnostic

Related Child Applications (1)

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US13/137,295 Division US8388934B2 (en) 2006-08-08 2011-08-04 Diagnostic agent

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US20090246135A1 true US20090246135A1 (en) 2009-10-01

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US12/310,019 Abandoned US20090246135A1 (en) 2006-08-08 2007-07-31 Diagnostic agent
US13/137,295 Expired - Fee Related US8388934B2 (en) 2006-08-08 2011-08-04 Diagnostic agent

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US (2) US20090246135A1 (ja)
EP (1) EP2050469B1 (ja)
JP (1) JP4719911B2 (ja)
KR (1) KR101429576B1 (ja)
WO (1) WO2008018327A1 (ja)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0503738D0 (en) 2005-02-23 2005-03-30 Optinose As Powder delivery devices
WO2010018723A1 (ja) * 2008-08-12 2010-02-18 マイラン製薬株式会社 液状インジゴカルミン製剤
US10463229B2 (en) * 2010-10-22 2019-11-05 Fukuoka University Endoscopic observation method and composition for improving diagnostic performance involving applying useful white opaque substance to diagnosis of gastric epithelial tumors (adenoma or gastric cancer)
AU2015212418B2 (en) * 2014-01-29 2020-01-23 Cosmo Technologies Limited Liquid composition in the form of emulsion or microemulsion for rectal administration containing at least one dye, and its use in a diagnostic endoscopic procedure of sigmoid colon and/or rectum

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040131501A1 (en) * 2002-08-28 2004-07-08 Yasuko Maruo Ozone gas sensing element, detection apparatus, and measurement method

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Publication number Priority date Publication date Assignee Title
JP3251186B2 (ja) 1997-01-10 2002-01-28 宗明 佐野 手術用生体マーキング製剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040131501A1 (en) * 2002-08-28 2004-07-08 Yasuko Maruo Ozone gas sensing element, detection apparatus, and measurement method

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JPWO2008018327A1 (ja) 2009-12-24
WO2008018327A1 (fr) 2008-02-14
KR101429576B1 (ko) 2014-08-12
JP4719911B2 (ja) 2011-07-06
EP2050469B1 (en) 2014-05-28
EP2050469A1 (en) 2009-04-22
US20110293523A1 (en) 2011-12-01
EP2050469A4 (en) 2011-04-06
KR20090053805A (ko) 2009-05-27
US8388934B2 (en) 2013-03-05

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Owner name: NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KAWAHARA, YOSHIROU;REEL/FRAME:022272/0881

Effective date: 20090123

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION